Background
Phase 3 international double-blind RCT; N=1306 metastatic hormone-sensitive prostate cancer (mHSPC); triplet darolutamide + ADT + docetaxel vs ADT + docetaxel.
Interventions and follow up
Arm A: Darolutamide 600 mg PO BID + ADT + docetaxel 75 mg/m2 q3wk
Arm B: Placebo + ADT + docetaxel
Primary endpoint: Overall survival
mFollow up: ~43.7 mo
Arm B: Placebo + ADT + docetaxel
Primary endpoint: Overall survival
mFollow up: ~43.7 mo
Results
mOS: NR vs 48.9 mo, HR 0.68, 95% CI 0.57–0.80, P<.001.
4yr OS: 62.7% vs 50.4%.
4yr OS: 62.7% vs 50.4%.
Adverse events
Grade 3–4 overall: 66.1% vs 63.5% (A vs B).
Hematologic (G3+): neutropenia 33.7% vs 34.2%; febrile neutropenia 7.8% vs 7.4%; anemia 4.8% vs 5.1%.
Cardiovascular: hypertension 6.4% vs 3.2%.
Hematologic (G3+): neutropenia 33.7% vs 34.2%; febrile neutropenia 7.8% vs 7.4%; anemia 4.8% vs 5.1%.
Cardiovascular: hypertension 6.4% vs 3.2%.
Conclusions
Adding darolutamide to ADT + docetaxel significantly prolonged OS in mHSPC without increasing overall toxicity, establishing triplet therapy as a standard option for fit patients.
Key Limitations
All patients received docetaxel, so triplet cannot be compared with ARPI + ADT doublet (no doublet-ARPI control); predominantly high-volume/de novo metastatic population limits generalizability; cumulative toxicity and cost of triplet; optimal patient selection (volume/risk) not fully defined.
Clinical Context
FDA approved darolutamide + docetaxel for mHSPC (Aug 2022); EMA approved 2022. ASCO and ESMO endorse triplet therapy (ARPI + ADT + docetaxel) for fit mHSPC patients, particularly high-volume/de novo disease; ARASENS and PEACE-1 underpin this recommendation.